Infectious organisms, particularly bacteria, are threatening almost every living thing including human, animals and plants. According to rapid global warming, new infectious organisms would emerge and thereby infectious diseases are increasing consistently. Threat by such infectious organisms is more serious than intractable disease such as cancer, diabetes mellitus, stroke and leukemia.
Antibiotics have been regarded as the drugs closely related to human health for almost 100 years. The first antibiotic to treat infectious disease caused by bacteria was penicillin isolated from Penicillium notatum by Alexander Fleming in 1920s. Since then, diverse antibiotics have been developed based on the structure of penicillin, which seems to free human from infectious bacteria that have annihilated tens of thousands people. However, before long, penicillin-resistant Staphylococcus aureus had been found and antibiotics could not be the final solution any more. After penicillin-resistant Staphylococcus aureus was found, methicillin was developed in 1960s, giving a new hope. But, again, MRSA (methicillin-resistant Staphylococcus aureus) was found in 1970s. So, since the first generation antibiotic, penicillin, was developed, reliable antibiotics having a satisfactory effect have not been developed because of resistance matter even if various attempts have been made to develop diverse antibiotics. And novel effective antibiotics are still being searched. Mankind developed vancomycin, the super-strong antibiotic, to cope with MRSA. However, VISA (vancomycin-intermediate Staphylococcus aureus) was found in Japan in 1997 and in Korea in 1998. And soon VRSA (vancomycin-resistant Staphylococcus aureus) was found in USA in 2002, which was a big issue then world widely. Even if antibiotics are still being used for the treatment of bacterial infectious disease, over-use or mis-use of antibiotics caused another problem of the generation of antibiotic resistant strains. Make matter worse, so called super-bacteria or super-bug which are resistant bacteria that nullify the treatment effect of the conventional antibiotics appeared, which is a serious social problem. Therefore, it is an urgent request to develop novel antibiotics that can treat infectious disease even caused by those bacteria having resistance against the conventional antibiotics.
The major reason of the increase of antibiotic resistant strains is antibiotic contamination of the environment including human, cattle, wild animals, cultured fishes, soil, river, and sea resulted from mis-use and over-use of antibiotics. Over-use of antibiotics is one reason for making resistance acquiring time in bacteria against newly developed antibiotics shorter than ever. But, fundamentally, most of new antibiotics have been based on the same basic structure as the conventional antibiotics and only a little modification in chemical structure has been made because of limitation in techniques. All the antibiotics on the market are facing resistance problem, and thus it is strongly required to develop a novel class antibiotic free from resistance problem of the conventional antibiotics. Novel class antibiotics developed for the last 50 years are only three, which are oxazoldinones, cyclic lipopeptides and platensimycin. It is thus still required to develop a novel class antibiotic and the novel class antibiotic is supposed to have antimicrobial activity to those bacteria having resistance against the conventional antibiotics.
Under the situation that the problem of the conventional antibiotics represented by mis- and over-use of antibiotics is international issue, bacteriophage and bacteriophage-originated lysin protein are drawing our attention as alternative antibiotics to solve the said problem. Bacteriophage and lysin protein are completely different from the conventional antibiotics class, which means they have completely different antibacterial mode of action. Therefore, it is expected that they can reduce side effects of the conventional antibiotics.
Bacteriophage is one of virus-like microorganisms infecting bacteria and generally called ‘phage’ in short. Bacteriophage is an organism having a simple structure wherein a central genetic material composed of nucleic acid is covered by a protein envelope. The nucleic acid is single stranded or double stranded DNA or RNA. To survive, bacteriophage needs a host bacterium and every bacterium has a specific partner bacteriophage. Bacteriophage destroys cell wall by attacking the peptidoglycan layer of cell wall. Bacteriophage was first found by Twort, an English bacteriologist. And in 1917, a French bacteriologist d'Herelle identified bacteriophage independently. The term bacteriophage means ‘eating bacteria’. Owing to antibacterial activity, bacteriophage has been used for the treatment of disease in human and animal right after it was identified. Since penicillin was found by Flemming, various antibiotics have been developed and distributed. So, bacteriophage became out of interest in Western countries. However, Russia and some East European countries including Germany have constantly studied bacteriophage and some of related products have been commercialized. In 2000s, antibiotic-resistant strains became recognized as a serious problem, and therefore Western countries began to be interested in bacteriophage. It was not until 7-8 years since then that cases of industrialization of bacteriophage have been reported. That is, bacteriophage became newly recognized world-widely in the early 2000, and it has been 7-8 years that industrialization of bacteriophage was attempted. But, it is still a novel field and is being actively advanced with the development of bioengineering techniques.
The most peculiar characteristic of bacteriophage is that bacteriophage infects pathogenic bacteria and then destroys cell wall of the bacteria to kill the bacteria at last. The cell killing mechanism by bacteriophage is completely different from the conventional synthetic antibiotic mechanism which is mainly to interrupt bacterial cell wall synthesis. So, bacteriophage can demonstrate antimicrobial activity regardless of sensitivity to the conventional synthetic antibiotics. That is, it shows antibacterial effect on such multi-drug resistant strains. Bacteriophage has a specific and unique antibacterial activity against bacteria. That is, it does not affect eukaryotic cells composing human and animals.
With the advance of bioengineering techniques, studies have been actively undergoing to treat infectious organisms using bacteriophage-originated lysin protein, known to play a key role in cell-destruction by bacteriophage. A report was published in Nature in 2002 saying that lysin protein could treat Bacillus anthracis effectively. Since then, bacteriophage-originated lysin protein became on the spotlight. Lysin protein also has completely different antibacterial mode of action, precisely lysin protein demonstrates its antibacterial activity by directly destroying bacterial cell wall, unlike the conventional antibiotics. Attempts to use lysin protein were rather made later than attempts to use bacteriophage itself. But studies on lysin protein having high potential as a treatment agent for infectious organism related disease have been actively undergoing.